Studies on the STAT6 Knockout Mouse : A Novel Animal Mode for Diabetes Mellitus Associated with Visceral Obesity Syndrome

STAT 6敲除（-/-）基因型在引入C57 BL/6背景后导致晚发型肥胖症的发展。在30周龄时，与雄性野生型小鼠相比，雄性STAT 6（-/-）小鼠的体重增加了39%，循环瘦素升高了约5倍。血浆总胆固醇和甘油三酯水平也升高。30 - 45周龄雄性STAT 6（-/-）小鼠表现出空腹和葡萄糖负荷后高血糖。雌性STAT 6（-/-）小鼠也比雌性野生型小鼠重，尽管差异小于雄性小鼠。糖尿病小鼠的组织学研究显示肝脂肪变性和β细胞增生伴失调。与野生型小鼠相比，雄性STAT 6（-/-）小鼠在糖尿病前期阶段的食物摄入量显著增加。这些结果表明，STAT 6信号通路不仅参与免疫应答的调节，而且还参与能量平衡和代谢的调控。(-790和-866），而在编码区没有检测到多态性。对105名瘦型（BMI <25）和77名肥胖型（BMI>30）受试者的基因分型表明，翻译起始位点-790处的近端多态性与肥胖显著相关（p=0.007），肥胖受试者中GT 18等位基因的比例显著较高（p=0.0095）。该多态性位点与男性肥胖显著相关，但与女性无关。单倍型之间的相对荧光素酶活性没有显著差异。然而，STAT 6基因是日本男性肥胖症发展的新候选基因。

The STAT6 knockout (-/-) genotype, upon introduction into the C57BL/6 background, results in the development of late-onset obesity. At 30 weeks of age, body weights of male STAT6 (-/-) mice, were increased, by 39% compared with male wild-type mice, with approximately five-fold elevation of circulating leptin. Plasma levels of total cholesterol and triglyceride were also increased. Thirty to 45-week-old male STAT6 (-/-) mice showed fasting and post-glucose load hyperglycemia. Female STAT6 (-/-) mice were also heavier than female wild-type mice, although the difference was smaller than that for male mice. Histological studies of diabetic mice showed hepatosteatosis and β-cell hyperplasia with deregulation. Food intake was significantly increased in male STAT6 (-/-) mice at the prediabetic stage when compared with wild-type mice. These observations indicate that STAT6 signaling is involved not only in the 'regulation of immune responses but also in the control of energy balance and metabolism.Screening of the human STAT6 gene for mutations showed two dinucleotide (GT) repeat polymorphic sites. (-790 and -866) in the putative promoter region, while no polymorphisms were detected in the coding region. Genotyping of 105 lean (BMI <25) and 77 obese (BMI>30) subjects demonstrated a significant association between the proximal polymorphism at-790 from the translation initiation site and obesity (p=0.007), with a significantly higher ratio of GT18 allele in obese subjects (p=0.0095). The polymorphic site was significantly associated with obesity in men but not in women. No significant difference was observed in the relative luciferase activity among the haplotypes. However, the STAT6 gene is a novel candidate gene for the development of obesity in Japanese men.